WO2010136847A1 - Metformine enrobée d'une solution de pioglitazone - Google Patents

Metformine enrobée d'une solution de pioglitazone Download PDF

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Publication number
WO2010136847A1
WO2010136847A1 PCT/IB2009/052200 IB2009052200W WO2010136847A1 WO 2010136847 A1 WO2010136847 A1 WO 2010136847A1 IB 2009052200 W IB2009052200 W IB 2009052200W WO 2010136847 A1 WO2010136847 A1 WO 2010136847A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
mixtures
solution
agent
insulin sensitizer
Prior art date
Application number
PCT/IB2009/052200
Other languages
English (en)
Inventor
Farhad Farshi
Recep Avci
Hasan Samuk
Serdar Soylemez
Fikret Koc
Erhan Koc
Original Assignee
Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to TR2012/02048T priority Critical patent/TR201202048T2/xx
Priority to PCT/IB2009/052200 priority patent/WO2010136847A1/fr
Publication of WO2010136847A1 publication Critical patent/WO2010136847A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to coating of biguanide antihyperglycaemic agents
  • insulin sensitizers such as thiazo- lidinediones ; pioglitazone hydrochloride
  • CompectactTM is prepared by separate granulation of pioglitazone and metformin and tabletting thereof.
  • Pioglitazone HCl is dissolved in a water miscible organic solvent / water/ acid mixture. More preferably Pioglitazone HCl is dissolved in Ethanol /water /diluted HCl in suitable proportions of the participant solvents to achieve a clear solution with suitable amount of total solvent used. Using less solvent amount is important due to shortening coat spraying times, saving solvent and such economical reasons. Using vast amounts of solvent would have also an effect on the dissolution and tabletting properties of the composition since Metformin HCl is fairly soluble in most organic solvents and water which would affect the consistency.
  • EP 0 861 666 discloses that excipients are added to the active component or components and the resulting composition is compressed. Where necessary, the compressed product is coated, by the per se known technique, for masking the taste or for enteric dissolution or sustained release ( page 2, 0020) .
  • EP 0 861 666 does not disclose that coating of metformin with pioglitazone hydrochloride solution.
  • EP 1 231 918 claims a pharmaceutical composition characterized by thiazo- lidinedione and metformin hydrochloride are each dispersed within its own pharmaceutically acceptable carrier in the pharmaceutical composition.
  • EP 1 231 918 points out that polyvinyl pyrollidone (or PVP) is particularly effective as a binder for use with metformin hydrochloride.
  • PVP polyvinyl pyrollidone
  • EP 1 231 918 delinetaes pioglitazone and metformin hydrochloride are each dispersed within its own pharmaceutically acceptable carrier in the pharmaceutical composition.
  • EP 1 231 918 does not disclose coating of metformin with pioglitazone hydrochloride solution.
  • EP 1 552 832 discloses a preparation coated with pioglitazone hydrochloride so as to obtain proper dissolution property of pioglitazone hydrochloride .
  • EP 1 552 832 it is described that coating of metformin tablets with pioglitazone hydrochloride which is in dispersion form. All of the examples and claims explain coating of metfomin tablets with pioglitazone hydrochloride. It is not disclosed that coating of metformin with pioglitazone hydrochloride solution.
  • polyvinylpyrrolidone , polyethylene glycol 6000 and pioglitazone hydrochloride were dispersed in ethanol to give a coating solution (page 8, line 25).
  • One aspect of this invention is coating of biguanide antihyperglycaemic agent with thiazolidinedione solution.
  • Thiazolidinedione may be pioglitazone or its salts (preferable hydrochloride), rosiglitazone or its salt (preferable maleate) or any other thiazolidinedione.
  • Biguanides may be phenformin, metformin, buformin, or a salt thereof (e.g., hydrochloride, fumarate, succinate) etc.
  • Preferredbiguanide is metformin or a salt thereof (preferably metformin hydrochloride).
  • Pharmaceutical formulations and combinations may contain further active ingredients along with them.
  • Pioglitazone hydrochloride solution may further include suitable excipients. The character of the solution isinsulin sensitizer is completelydissolved.
  • Organic solvents used in preparation of solution are ,but not limited to, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, 2-methyl-l-propanol etc. ; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc. ; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate etc. ; hydrocarbons such as heptane ; halogenated hydrocarbons such as dichloromethane.
  • the organic solvent is preferably an alcohol and more preferably methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol and the so on. Ethyl alcohol is mostly preferred.
  • Organic solvents can be used alone or in combination with water.
  • organic acids are formic acid, acetic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, p- toluenesulfonic acid .
  • inorganic acid is hydrochloric acid which is in the form of solution in water.
  • Mixtures of organic solvents may also be used. Using of mixtures of organic solvents can be in an appropriate ratio. Mixtures may contain water.
  • the percentages pioglitazone / water / organic solvent / hydrochloric acide is critical due to poor solubility of pioglitazon hydrochloride and need for low solution amount.
  • the solution comprising insulin sensitizer is in the range of from 0.01 % to 9.00 %
  • water is in the range of from 00.00 % to 70 %
  • organic solvent or mixtures of organic solvents are in the range of from 20 % to 75 %
  • acid or mixtures of acids are in the range of from 0.05 % to 50 % by weight
  • binder or mixtures of binders are are in the range of from 5 % to 35.
  • Weight of acid is based on real amount of said acid.
  • the binder which is used in preparation solution, may be, but not limited to, starch, polyethyleneglycol, microcrystalline cellulose, hydroxypropyl cellulose, hydrox- ypropylmethyl cellulose,carboxymethylcellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof.
  • Preferred binder is polyethyleneglycol or povidone or mixtures thereof .
  • the solution can also be prepared without binder or mixtures of binders.
  • the pioglitazone hydrochloride solution of the present invention may contain further excipient or excipients.
  • This invention describes coating particles of biguanide antihyperglycaemic agent with thiazolidinedione solution.
  • this invention embraces every kind of particles which include particles of biguanide antihyperglycaemic agent. It means that direct compression (DC) forms of biguanide antihyperglycaemic agent may also be used. DC forms are available on the market. In case of using DC forms of biguanide antihyperglycaemic agent , biguanide antihyperglycaemic agent particles adhere to other excipient or excipients.
  • DC direct compression
  • biguanide antihyperglycaemic agent may be granulated with suitable excipient or excipients and then thiazolidinedione solution coating may be administered according to this invention .
  • Particles of biguanide antihyperglycaemic agent alone may also be coated .
  • Coexisting particles ,whatsoever, of biguanide antihyperglycaemic agent with other excipient or excipients can be coated according to this invention.
  • Compressed dosage forms of biguanide antihyperglycaemicagent or pellets and dosage forms prepared by using this pellets of biguanide antihyperglycaemic agent can also becoated.
  • this invention embraces a method of coating of biguanide particles with thiazolidinedione solution.
  • Method of coating has following steps ;
  • Hydrochloride particles in fluid bed or any other suitable vehicle Hydrochloride particles in fluid bed or any other suitable vehicle .
  • composition includes coating of metformin particles with pioglitazone hydrochloride solution shows same or identical and suitable dissolution properties when compared to reference (CompetactTM) product .
  • pharmaceutical formulation exhibits a dissolution profile which has similarity factor (f2) of at least 50 to 100 in dissolution environments when compared to the reference (Competact TM ) dissolution profile.
  • Preferred dissolution mediums are 0.1 NHCI, pH 2.5, pH 4.5 and pH 6.8 . Dissolution tests are performed by a USP Method II - Paddle method at 37 0 C, 50 rpm,900 ml. As an exemplary dissolution profile in pH 2.5 medium is given ( Figure 1).
  • Pharma- ceutical formulations may be in the form of such as tablet, bilayer or trilayer tablet, caplet, capsule, granule, powder etc. These forms may be a controlled release, immediately release , sustained release, modified release and the like. Formulations may include excipients as disintegrants, binders, lubricants, coloring agents, pH regulators, surfactants, stabilizers, flavours, coating agents and the like . Pharmaceutical formulations should contain both at least a biguanide antihyperglycaemic agent and at least a thiazolidinedione agent. Further active pharmaceutical ingredient may be present in formulations and combinations.
  • Disintegrants are such as but not limited to carboxymethyl cellulose, calcium car- boxymethyl cellulose, sodium carboxymethyl starch, modified starches, sodium starch glycolate, croscarmellose sodium, crospovidone, hydroxypropyl cellulose et.
  • Preferred disintegrant is croscarmellose sodium.
  • Binders are such as but not limited to starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof, etc.
  • Preferred binder is microcrystalline Cellulose .
  • Fillers are lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch or mixtures thereof.
  • Preferred filler is lactose.
  • Lubricants are magnesium stearate, magnesium lauryl sulphate,sodium stearyl fumarate, polyethylene glycol, stearic acid, colloidal silicon dioxide or mixtures thereof.
  • Preferred lubricant is magnesium stearate
  • the coating agent that can be used includes, for instance, ethylcellulose, hydrox- ymethylcellulose, polyethylene glycol, cellulose acetate phthalate, hydroxypropyl- methylcellulose phthalate, and Eudragit. Coating may further contain an excipient, for example, titanium oxide, talc, ferric oxide and the like. As a coating agent multifunction ingredient such as Opadry ® White YS-1R-7002 can also be used.
  • phase B has following steps ;
  • metformin hydrochloride is from 70 to 90 %
  • pioglitazone hydrochloride is from 1 to 5 %
  • binder is from 5 to 15 %
  • filler is from 1 to 5 %
  • disintegrant is from 2 to 10 %
  • lubricant is from 0,1 to 5 %
  • coating agent is from 0.5 to 5 % by the total weight of the pharmaceutical formulation.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne l'enrobage d'agents antihyperglycémiants de type biguanide (tels que le chlorhydrate de metformine) avec une solution de sensibilisants à l'insuline (tels que les thiazolidinediones ; le chlorhydrate de pioglitazone).
PCT/IB2009/052200 2009-05-26 2009-05-26 Metformine enrobée d'une solution de pioglitazone WO2010136847A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
TR2012/02048T TR201202048T2 (tr) 2009-05-26 2009-05-26 Pioglitazon çözeltisi ile kaplanmış metformin.
PCT/IB2009/052200 WO2010136847A1 (fr) 2009-05-26 2009-05-26 Metformine enrobée d'une solution de pioglitazone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2009/052200 WO2010136847A1 (fr) 2009-05-26 2009-05-26 Metformine enrobée d'une solution de pioglitazone

Publications (1)

Publication Number Publication Date
WO2010136847A1 true WO2010136847A1 (fr) 2010-12-02

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PCT/IB2009/052200 WO2010136847A1 (fr) 2009-05-26 2009-05-26 Metformine enrobée d'une solution de pioglitazone

Country Status (2)

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TR (1) TR201202048T2 (fr)
WO (1) WO2010136847A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035940A2 (fr) * 1999-11-16 2001-05-25 Smithkline Beecham P.L.C. Nouvelle composition et utilisation
WO2001082875A2 (fr) * 2000-05-01 2001-11-08 Aeropharm Technology, Inc. Formulation de noyau
WO2003005991A1 (fr) * 2001-07-10 2003-01-23 Aeropharm Technology Incorporated Formulation de noyau
WO2004101561A1 (fr) * 2003-05-13 2004-11-25 Synthon B.V. Sels de pioglitazone tels que le sulfate de pioglitazone, et leurs compositions pharmaceutiques et leurs procedes d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035940A2 (fr) * 1999-11-16 2001-05-25 Smithkline Beecham P.L.C. Nouvelle composition et utilisation
WO2001082875A2 (fr) * 2000-05-01 2001-11-08 Aeropharm Technology, Inc. Formulation de noyau
WO2003005991A1 (fr) * 2001-07-10 2003-01-23 Aeropharm Technology Incorporated Formulation de noyau
WO2004101561A1 (fr) * 2003-05-13 2004-11-25 Synthon B.V. Sels de pioglitazone tels que le sulfate de pioglitazone, et leurs compositions pharmaceutiques et leurs procedes d'utilisation

Also Published As

Publication number Publication date
TR201202048T2 (tr) 2012-04-24

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